Triosephosphate isomerase barrel

Normal mode analysis of the mechanical properties of a triosephosphate isomerase-barrel protein suggests that the region between the secondary structures plays an important role in the dynamics of the protein. The beta-barrel region at the core of the protein is found to be soft in contrast to the helical, strand and loop regions [62]. A detailed discussion of other properties of proteins is mechanically highly non-linear systems is given by Kharakoz [63]. 

Table 4.1 The amino acid residues of the eight parallel p strands in the barrel structure of the enzyme triosephosphate isomerase from chicken muscle...

Parallel /3 structure usually forms large, moderately twisted sheets such as in Fig. 23, although occasionally it rolls up into a cylinder with helices around the outside (e.g., triosephosphate isomerase). Large antiparallel sheets, on the other hand, usually roll up either partially (as in the first domain of thermolysin or in ribonuclease) or completely around to join edges into a cylinder or barrel. Occurrence, topology, and classification of /3 barrels will be discussed in Section III,D, but here we will consider the interaction between the /3 sheets on opposite sides of the barrel, especially in terms of the angle at which opposite strands cross. 

Fig. 29. An assortment of/3 barrels, viewed down the barrel axis (a) staphylococcal nuclease, 5-stranded (b) soybean trypsin inhibitor, 6-stranded (c) chymotrypsin, 6-stranded (d) immunoglobulin (McPC603 CH1) constant domain, 7-stranded (e) Cu,Zn superoxide dismutase, 8-stranded (f) triosephosphate isomerase, 8-stranded (g) im-... 

A. Singly wound parallel /3 barrels Triosephosphate isomerase Pyruvate kinase domain 1 KDPG aldolase ( )... 

Fic. 90. Triosephosphate isomerase as an example of a singly wound parallel /3 barrel, (a) a-Carbon stereo, viewed from one end of the barrel (b) backbone schematic, viewed as in a (c) a-carbon stereo, viewed from the side of the barrel (d) backbone schematic, viewed as in c (e) topology diagram showing the + lx right-handed connections between the fi strands. 

The enzyme triosephosphate isomerase, abbreviated to TIM, was found to have an important type of structure, now called an a//3 or TIM barrel, consisting of at least 200 residues. In its idealized form, the barrel consists of eight parallel /3 strands connected by eight helixes (Figure 1.19). The strands form the staves of the barrel while the helixes are on the outside and are also parallel (Figure 1.20). (3 strands 1 and 8 are adjacent and form hydrogen bonds with each other. The center of the barrel is a hydrophobic core composed of the side chains of alternate residues of the strands, primarily those of the branched... 

Figure 1.20 The archetypal /3 barrel, a monomer of triosephosphate isomerase (TIM) drawn in MoiScript.

Lack of congruence of structure and mechanism Common structure does not imply a common mechanism The /1-barrel structures triosephosphate isomerase and xylose isomerase function by hydride transfer through enol, whereas aldose reductase performs hydride transfer through a metal ion. 

Fig. 4-10 Topology diagram for (a) retinol binding protein (RBP) and (b) triosephosphate isomerase (TPI). The arrows represent p strands (numbered from N to C) and the dark boxes represent a helices. Note from Fig. 4-8 that both of these proteins form a barrel structure comprised of eight p strands with the first strand hydrogen bonded to last strand in order to "close the barrel. However, whereas the p strands are antiparallel in RBP, they are arranged in parallel in TPI and are surrounded by an outer layer of a helices which connect each p strand to the next in the barrel.

In principle, nature has decoupled protein function and protein fold. The most commonly known example for a fold conveying a broad variety of functions is the TIM barrel. First found in triosephosphate isomerase, the TIM barrel also occurs in proteins as diverse as aldose reductase, enolase, and adenosine deaminase (see, e.g., the review by Nagano et al. [104]). To date, the TIM barrel fold, as a generic scaffold, is associated with 15 different types of enzymatic functions. 

Figure 13.1. Structural classes of protein folds, showing how the folds can be classified into different structural classes. Top row the three basic fold classes a, containing only a helices a and p, containing a helices and p sheets and p, containing only p sheets. Middle row three different architectural subclasses of the a and p class triosephosphate isomerase (TIM) barrel, three-layer sandwich, and roll. Bottom row two different arrangements of the "three-layer sandwich . The spiral conformations are the a helices, and the broad arrows are the p sheets. (From Orengo, C. A., Michie, A. D., Jones, S. et al. [1997]. CATH - a hierarchic classification of protein domain structures [Figure 2]. Structure, 5, 1093-108. Copyright 1997, Elsevier Science. Reprinted with permission.)...

Enoyl-ACP reductases catalyze the terminal reaction in the fatty acid elongation cycle (Figure 1). Currently, four known families of enoyl-ACP reductases have been identified in microorganisms, encoded by xhe fabi, fabL, fabK, and fabV genes. ° " FabK is a flavin-containing triosephosphate isomerase (TIM)-barrel enoyl-ACP reductase, first identified in S. pneumoniae whereas FabI, FabV, and FabL are all members of the SDR family. FabI is the most intensively studied enoyl-ACP reductase, first identified in E. coli and Salmonella typhimurium as the product of the envM gene. ° In these initial studies, it was demonstrated that treatment with the... 

The X-ray crystal structure of P. putida muconate lactonizing enzyme (cycloisomerase) was determined in 1987, and was found to contain an a/(i barrel fold, also found in triosephosphate isomerase and enolase. Remarkably, the structure of P. putida mandelate racemase, which catalyzes a mechanistically distinct reaction earlier in the same pathway, was found in 1990 to have a homologous structure, indicating that the structural fold of the enolase superfamily is able to support a range of enzyme-catalyzed reactions. The P. putida 3-carboxy- r, x-muconate lactonizing enzyme, in contrast, shares sequence similarity with a class II fumarase enzyme, and determination of its structure in 2004 has shown that it shares the same fold as the class II fumarase superfamily, hence these two catalysts of similar reactions have evolved from different ancestors. ... 

The protein-building principles that have been described so far are sufficient for the construction of a ( a) barrel, otherwise known as a TIM barrel (the acronym TIM denoting triosephosphate isomerase, the first protein found to contain this structure [126]). The (/J )g barrel is a common structure [127-129], found in about 20 different proteins to date (see Table 2) [22, 23, 126-170]. It... 

The ODCase monomer adopts a triosephosphate isomerase (TIM) fold, with a-helices surrounding an eight-stranded 8-barrel (Fig. 1). 

Triosephosphate isomerase was the first enzyme shown to contain an (a//3)g barrel and thus established this motif as the TIM barrel. This fold consists of eight parallel /3-strands connected by right-handed helical crossovers and is one of the most common folds found in enzymes. The TIM barrel typically contains approximately 200 amino acid residues. Contrary to the appearance of the ribbon drawing (Fig. 14a), the interior of the barrel is closely packed by the side chains protruding from the /3-strands. The strands are inclined at an angle of approximately 30° to barrel axis, which is necessary to allow efficient packing of the interior. The necessity to form a closely packed interior explains why these barrels are almost always formed from eight strands. There are several variations on the TIM barrel that include the addition and subtraction of j8-strands as well as the introduction of antiparallel /3-strands as observed in enolase. These variations attest to the versatility of this fold. 

A major advancement is the elucidation of the structure of V. harveyi luciferase, at 2.4 A and 1.5 A resolution, " with key structural features summarized and discussed. Each subunit assumes a (P/a)g barrel structure, originally shown for the structure of triosephosphate isomerase (TIM). There are considerable structural similarities between the a and P subunits the main chains of these two subunits show good superposition."" The structure of V. harveyi luciferase Pj was also solved. " The four C-terminal residues (321-324) of P that are not resolved in the original aP structure were determined. In general, the secondary and tertiary structures of Pj are quite similar to those of ap. The intersubunit areas for P2 and aP are also similar, except that the former is smaller. The two subunits in Pj are highly homologous but not identical in structure the root-mean-square difference between the main P chains in P2 is 0.45 k7 A possible FMN site in P2 is discussed. 

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